Abstract

Aging is the gradual decline of physiological functions and organismal fitness, which leads to age-dependent fitness loss, diseases and eventually mortality. Understanding the cause of aging constitutes one of most intriguing areas of research in biology. On both the cellular and molecular levels, it has been hypothesized that there are aging determinants to control the onset and progression of aging, including the loss of beneficial components and accumulation of detrimental factors. This Review highlights the recent advance in identifying various factors that affect the aging process, focusing on how these determinants affect the lifespan and fitness of a cell or organism. With more and more aging determinants revealed, further understanding about their functions and interconnections could enable the development of specific intervention to extend healthy lifespan and reduce the risk of age-related diseases.

Balance between beneficial and detrimental factors during aging. Declining levels or activities of beneficial factors and accumulation of detrimental factors during aging lead to fitness collapse at the cellular level. The scheme enumerates several beneficial and detrimental factors during lifespan as described in this Review. Beneficial factors include rejuvenation molecules such as TIMP2 (others in ), damage clearance mechanisms and organelle functions, whereas detrimental factors include DNA damage, protein aggregates and the micro-environment created by senescent cells. Illustrated below are the typical cellular changes during aging that are mediated by the decreased level or activity of beneficial molecules. For instance, mitochondrial functions decline, including the accumulation of mutations in mitochondrial DNA. In addition, the lysosomal pH increases with a resulting decrease in its degradation capacity (dark gray circles in aged cell). Furthermore, there is also a loss of nuclear integrity and genome stability, as well as a shortening of telomeres and an accumulation of protein aggregates.

The ability of cells to degrade aggregates declines during aging. Structurally unstable proteins misfold under stress and form heterogeneous aggregates. Chaperone machineries assist in the refolding of misfolded proteins and participate in sending them to different degradation systems (not shown in the figure). In young cells with highly functional cellular machineries, aggregated proteins are efficiently degraded by autophagy through the lysosome system, by the ubiquitin-proteasome system (UPS), and by mitochondrial import and degradation (MAGIC). However, in aged cells, these machineries decline in function. For example, the reduced membrane potential of mitochondria in the aged cell may also lead to reduced import. The activities of UPS and lysosomal proteolysis may also decline during aging due to a decrease in cellular ATP levels and increased lysosomal pH, respectively. The accumulation of aggregates in aged cells then can impair other cellular functions and lead to fitness decline and cell death.

Detrimental effects of senescent cells in aged organisms. Different stressors encountered during aging, such as telomere erosion, DNA damage, oxidative stress, oncogene activation and/or tumor suppressor loss, and others, can all cause cellular senescence. The failed clearance of the senescent cells during aging can be detrimental, as they may cause anatomic lesions, such as build up of an atherosclerotic plaque, disrupt tissue homeostasis by occupying physiological niches or result in a loss of the regeneration capacity of the tissue, such as in T cells and pancreatic β cells (for details please see the review, ). Furthermore, the secretome of senescent cells can be toxic to other cells.